Phase I results have demonstrated the feasibility of synthesizing phosphate-linked dimers of specific dideoxynucleosides which exhibit anti- HIV activity. The dimers showed enhanced activity and less cytotoxicity in in vitro assays when compared to combinations of the parent drugs. The results suggest that lower amounts of dimer may be required to achieve an optimal anti-HIV effect. Also viral resistance to AZT may not extend to the dimers because there appears to be no cross-resistance between AZT and ddA AZT-P-ddI for further evaluation. In Phase II, it is proposed to synthesize its uptake and tissue distribution after iv and po administration to rats. Pharmacokinetics and toxicity (acute and chronic) will also be evaluated. Intracellular levels of AZT-P-ddI and metabolites will be quantitated in primary human lymphocytes and compared to values obtained for AZT and ddI. The prophylactic and therapeutic efficacy of AZT-P-ddI in mice inoculated with a Friend retrovirus will be evaluated. The EC50 of AZT-P-ddI in AZT resistant and sensitive HIV strains will be determined. The results obtained from the proposed phase II studies will provide support for the entry of this agent into clinical trials.